Does VEGF facilitate local tumor growth and spread into the abdominal cavity by suppressing endothelial cell adhesion, thus increasing vascular peritoneal permeability followed by ascites production in ovarian cancer?

Ovarian cancer is mostly associated with pathologically regulated permeability of peritoneal vessels, leading to ascites. Here, we investigated the molecular regulation of endothelial permeability by the vascular endothelial growth factor (VEGF) and both tight and adherens junction proteins (VE-cadh...

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Bibliographic Details
Published in:Molecular cancer 2016-02, Vol.15 (13), p.13-13, Article 13
Main Authors: Bekes, Inga, Friedl, Thomas W P, Köhler, Tanja, Möbus, Volker, Janni, Wolfgang, Wöckel, Achim, Wulff, Christine
Format: Article
Language:English
Subjects:
Abdominal Cavity - pathology
Aged
Analysis
Antigens, CD
Ascites - pathology
Cadherins
Capillary Permeability
Care and treatment
Cell Adhesion
Cell Proliferation
Claudin-5 - metabolism
Coculture Techniques
Complications and side effects
Female
Gene expression
Health aspects
Human Umbilical Vein Endothelial Cells - pathology
Humans
Middle Aged
Neoplasm Grading
Neoplasm Invasiveness
Neoplasm Staging
Ovarian cancer
Ovarian Neoplasms - pathology
Ovarian Neoplasms - surgery
Peritoneum - blood supply
Peritoneum - pathology
Vascular endothelial growth factor
Vascular Endothelial Growth Factor A - blood
Vascular Endothelial Growth Factor A - metabolism
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Summary:Ovarian cancer is mostly associated with pathologically regulated permeability of peritoneal vessels, leading to ascites. Here, we investigated the molecular regulation of endothelial permeability by the vascular endothelial growth factor (VEGF) and both tight and adherens junction proteins (VE-cadherin and claudin 5) with regards to the tumor biology of different ovarian cancer types. Serum and ascites samples before and after surgery, as well as peritoneal biopsies of 68 ovarian cancer patients and 20 healthy controls were collected. In serum and ascites VEGF protein was measured by ELISA. In peritoneal biopsies co-localization of VE-cadherin and claudin 5 was investigated using immunohistochemical dual staining. In addition, the gene expression of VE-cadherin and claudin 5 was quantified by Real-time PCR. Differences in VEGF levels, VE-cadherin and claudin 5 gene expression were analyzed in relation to various tumor characteristics (tumor stage, grading, histological subtypes, resection status after surgery) and then compared to controls. Furthermore, human primary ovarian cancer cells were co-cultured with human umbilical vein endothelial cells (HUVEC) and changes in VE-cadherin and claudin 5 were investigated after VEGF inhibition. VEGF was significantly increased in tumor patients in comparison to controls and accumulates in ascites. The highest VEGF levels were found in patients diagnosed with advanced tumor stages, with tumors of poor differentiation, or in the group of solid / cystic-solid tumors. Patients with residual tumor after operation showed significantly higher levels of VEGF both before and after surgery as compared to tumor-free resected patients. Results of an immunohistochemical double-staining experiment indicated co-localization of VE-cadherin and claudin 5 in the peritoneal vasculature. Compared to controls, expression of VE-cadherin and claudin 5 was significantly suppressed in peritoneal vessels of tumor patients, but there were no significant differences regarding VE-cadherin and claudin 5 expression in relation to different tumor characteristics. A significant positive correlation was found between VE-cadherin and claudin 5 expression. VEGF inhibition in vitro was associated with significant increase in VE-cadherin and claudin 5. Our results indicate that increased peritoneal permeability in ovarian cancer is due to down-regulation of adhesion proteins via tumor derived VEGF. Advanced ovarian cancer with aggressive tumor biology
ISSN:1476-4598
1476-4598
DOI:10.1186/s12943-016-0497-3